This is a reverse translational project designed to unravel mechanisms underlying the impact of chronic pain on fundamental cortical functions, and to explore novel pharmacological manipulations potentially leading to novel therapeutics for alleviating neuropathic pain. The proposal is inspired by our human brain imaging studies that suggest a bidirectional interaction between neuropathic pain and emotional learning and memory, through the impact of pain on the prefrontal cortex. This project addresses these issues mechanistically in rodent models of persistent pain by 1) documenting deficits in emotional learning and memory; 2) relating such deficits to prefrontal cortical neuronal activity; 3) identifying the spatiotemporal pattern of brain regional changes in phenotype, in NMDA and AMPA expression, and cytokine expression, and 4) contrasting these outcomes between rodent models for neuropathic pain and persistent inflammatory pain. In Aim 1 we will examine the impact of neuropathic and inflammatory rodent models of persistent pain on emotional learning and memory, by assessing behavior on fear and reward conditioned-learning behavior. We also test the influence of chronicity of pain (that is duration from initial peripheral injury) on emotional learning and memory. We will also examine electrophysiological properties of prefrontal neurons in neuropathic rats in relation to pain and fear behaviors. Our preliminary results already indicate that neuropathic injured rats show: 1) reduced extinction of long-term fear memory, 2) reduced motivation in reward consumption, and 3) reduced reward seeking behavior; while inflammatory injured rats show reduced extinction for short-term fear memory. In Aim 2 we will study the effects of pharmacological manipulations, which modulate glutamatergic transmission in the prefrontal cortex, on neuropathic and inflammatory pain and on learning and memory. Our studies show that repeated oral D-cycloserine in neuropathic rats reduces the signs of pain behavior for weeks after stopping drug administration, 2) these effects are reproduced by acute infusion of D-cycloserine in either the medial prefrontal cortex or the amygdala, 3) acute infusion of D-cycloserine in medial prefrontal cortex completely reverses the injured paw dependent operant aversion behavior. We will extend these findings by examining effects of effects of a glycine transporter blocker (sarcosine) on the same paradigms. In Aim 3 we will study expression and role of brain-borne cytokines in neuropathic and inflammatory pain. The functional role of cytokines will be studied in persistent pain models, when cytokine receptor antagonist or cytokine blocking adenovectors are injected at specific brain sites. Recent findings indicate that brain-borne cytokines, such as IL-1 and IL-6, can affect synaptic plasticity, which depends on the stimulation of NMDA receptors. Consistently, it is also known that these mediators can affect behavior, learning and memory. Moreover, we now have results regarding cytokine expression in neuropathic rats and modulation of neuropathic pain behavior following blockade of cortical cytokines. PUBLIC HEALTH RELEVANCE: The overall purpose of this proposal is to understand the interaction between persistent pain and cortical cognitive mechanisms. The long-term objective is to develop novel drug therapies that act specifically at the cortical level and potentially reduce the suffering associated with chronic pain. Moreover, we seek to identify the role of endogenous cytokines, as markers for plasticity and learning, in the chronic pain. .